Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30536 (PBS)
 9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-alpha (TNF alpha) and nitric oxide (NO) mediate in part the microbicidal response of murine and rodent alveolar macrophages (AM) and recruited neutrophils (PMN) to airborne infections. Ethanol (ETOH) suppresses intrapulmonary TNF alpha and NO release and impairs pulmonary host defense mechanisms. We tested the concept that ETOH down-regulates NO by inhibiting production of TNF alpha. Male rats were given intratracheal (i.t.) saline (PBS), a polyclonal anti-TNF alpha antibody (TNFab) or nonimmune IgG (22 mg/kg, i.m.) 2 h before giving i.t. Escherichia coli endotoxin (LPS) to normal rats or rats pretreated with ETOM (5.5 g/kg, i.p.) 30 min before experimentation. AM and PMN were obtained from the bronchoalveolar lavage fluid (BAL) fluid of rats killed 2 and 4 h after administration of LPS. mRNA for inducible NO synthase (iNOS) and TNF alpha were measured in AM and PMN with competitor equalized RT-PCR techniques. The BAL fluid, AM, and PMN were assayed for TNF alpha and NO2-, and NO3- (RNI) with the L929 bioassay and chemiluminescence, respectively. TNFab abolished LPS-induced increases in TNF alpha but did not suppress the NO content of the BAL fluid or gene expression for iNOS by AM or PMN. ETOH suppressed LPS-induced increases in mRNA for iNOS, production of RNI, and BAL fluid TNF alpha but did not affect LPS-induced increases in mRNA for TNF alpha. ETOH-induced attenuation of LPS-induced up-regulation of the iNOS system did not differ in rats pretreated with TNFab or IgG. Thus, ETOH down-regulates iNOS gene expression and RNI production independent of its effects on TNF alpha. Acute ETOH administration suppresses iNOS at the level of transcription and TNF alpha at the level of translation or release of the peptide.
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PMID:Independent suppression of nitric oxide and TNF alpha in the lung of conscious rats by ethanol. 754 Jan 57

There is controversy regarding the evidence for the production of nitric oxide (NO) by neutrophils (PMNs). The present study investigates NO production, as assessed by the biosynthesis of the end products, nitrite and nitrate, in the pellets and supernatants of rat and mouse peripheral blood neutrophils obtained during endotoxemia and of peritoneal carrageenin-elicited PMNs stimulated in vitro with E. coli lipopolysaccharide (LPS). We also investigated the induction of NO synthase by rat and mouse peritoneal cells. The intraperitoneal (ip) administration of LPS to mice (10 mg/kg) and rats (5 mg/kg) significantly increased plasma nitrate concentration by six and 23-fold, respectively. In vivo pretreatment with L-NGmonomethyl arginine (L-NMMA) significantly inhibited this production. Compared to animals injected with PBS, the cell pellets of blood PMNs obtained from mice, but not rats, 2 or 6 h after LPS administration produced significant amounts of nitrite (14 +/- 3 and 18 +/- 2 nmol/mg protein, respectively). Little or no nitrite was found in the incubating medium. In contrast, 6 h after a carrageenin challenge (700 micrograms) peritoneal neutrophils obtained from rats, but not mice, released high concentrations of nitrite into the supernatant during a 24-h period of incubation (34 +/- 0.8 microM). The nitrite concentration of the pellet of these cells was negligible. In contrast to the lack of increase in the amount of nitrite released into the supernatants, the in vitro stimulation of rat PMNs with LPS (10 micrograms/ml) for 24 h did increase intracellular nitrite concentration (from 0.8 +/- 0.07 to 8 +/- 0.3 nmol/mg protein). In mouse PMNs, LPS treatment caused only a small release of nitrite into the incubation medium (14 +/- 1 microM). There was no significant change in nitrite concentration in the cell pellets. These data suggest that rat and mouse neutrophils differ in their ability to produce nitric oxide following stimulation with endotoxin.
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PMID:Differential production of nitric oxide by endotoxin-stimulated rat and mouse neutrophils. 873 34

Transient cerebral ischemia in fetal sheep is followed by a period of delayed cerebral injury associated with cerebral vasodilation. As nitric oxide (NO) can mediate both vasodilation and neuronal death, this study investigated whether inhibition of NO synthesis would attenuate the vasodilation and decrease cerebral injury. Eleven late gestation (range 122-133 d) fetal sheep were subjected to 30 min of transient cerebral ischemia in utero. Two hours later, treatment group (n = 5) received a continuous infusion of NG-nitro-L-arginine (L-NNA) at a dose of 50 mg.h-1 for 4 h followed by 20 mg.h-1 for the subsequent study period, a competitive inhibitor of NO synthase (NOS), whereas a control group (n = 6) received PBS. Inhibition of NOS activity was confirmed in the treatment group by 1) suppression of the fall in mean arterial blood pressure (MAP) associated with acetylcholine (p < 0.01), and 2) persistent increase in MAP after commencement of L-NNA (p < 0.05). Changes in cerebral blood volume (CBV) were observed for 3 d by measuring changes in concentration of total cerebral Hb ([tHb]) using near infrared spectroscopy. The delayed increase in CBV commenced at 13.1 +/- 1.0 h postischemia in the control and 12.7 +/- 2.3 h in the treatment group. Maximum increase at 30-36 h was 0.5 +/- 0.1 mL.100 g-1 in the treatment group and 1.2 +/- 0.2 mL.100 g-1 in the control (p < 0.05). Final CBV was depressed below preischemic baseline in the treatment (-0.7 +/- 0.2 mL.100 g-1) but not the control group (-0.1 +/- 0.3 mL.100 g-1) (p < 0.05). Neuronal loss, quantified histologically 3 d postischemia, indicated that cerebral injury was increased in the treatment group (p < 0.05). The results indicate that after transient cerebral ischemia in fetal sheep, NOS inhibition attenuates the delayed rise in CBV but does not decrease the extent of cerebral injury.
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PMID:Nitric oxide synthase inhibition attenuates delayed vasodilation and increases injury after cerebral ischemia in fetal sheep. 882 65

Ethanol (ETOH) inhibits the immune response to endotoxemia. The early stage of endotoxin (LPS)-induced shock is associated with an acute phase cardiovascular depression (APCD). Release of platelet activating factor (PAF) and tumor necrosis factor alpha (TNF alpha) with upregulation of nitric oxide (NO) production may initiate the APCD. Since ETOH inhibits induction of NO synthase (iNOS) mNRA by LPS, we postulate that ETOH may mask the APCD associated with endotoxemia. To test this, Sprague-Dawley rats (280-320 g, n = 5-6/group) were given LPS [0.75 mg/kg, intravenously (i.v.)] or PAF (10 to 150 micrograms/kg, i.v.) 30 min after administration of sterile saline (PBS), BN-5073 a mixed PAF antagonist (0.50 microgram/kg, i.v.), or ETOH [2.2-5.5 g/kg, intraperitoneally (i.p.)]. Cardiovascular parameters and plasma concentrations of nitrate and nitrite (RNI), ETOH, TNF alpha, and neutrophil (PMN) generation of RNI were measured. LPS and PAF both produced APCD. LPS-induced APCD was associated with tachycardia, elevated plasma TNF alpha and RNI, and ex vivo generation of RNI by PMNs. ETOH and BN-50730 prevented LPS-induced APCD and increases in RNI and TNF alpha. ETOH, however, increased the mortality associated with APCD. PAF produced only hypotension, bradycardia and elevated plasma levels of TNF alpha. ETOH and LNMMA did not affect PAF-induced APCD. BN-50730 inhibited PAF-induced APCD and plasma TNF alpha. We conclude that 1) ETOH inhibits the APCD and induction of NO characteristic of endotoxemia and 2) ETOH-induced suppression of LPS-mediated APCD may be mediated in part by suppression of release of intracellular PAF. Ethanol may increase the morbidity and mortality of endotoxemia by masking the hypotension and humoral changes characteristic of early endotoxemia thereby delaying appropriate therapy and by diminution of the protective effects of endogenous NO.
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PMID:Ethanol suppresses endotoxin but not platelet activating factor-induced hypotension and nitric oxide. 890 80

Excitotoxic amino acids, such as glutamate, may play an important role in retinal ischemia/reperfusion damage. In central neurons, excitotoxicity may be mediated by nitric oxide synthase (NOS) causing DNA damage via nitric oxide (NO). The nicked DNA activates poly-adenosine diphosphate (ADP)-ribose polymerase (PARP) and may deplete intracellular ATP resulting in cell death. PARP may also be involved in apoptosis. We used 3-aminobenzamide (3-ABA), a PARP inhibitor, to examine the possible involvement of PARP in a rat model of retinal ischemia. Retinal ischemia was induced by elevating the intraocular pressure (IOP) through the insertion of a needle into the anterior chamber of a rat eye. IOP was raised to 110 mm Hg for 60 minutes. Animals were given intracameral infusion of 0, 1, 3, 10, 30, 100 mM 3-ABA in 0.1 M PBS, pH 7.4 during ischemia. Morphologic and morphometric evaluation at 7 days after reperfusion showed that 3-ABA at 3 mM and above significantly ameliorated the ischemic/reperfusion damage to the retina. In addition, at 10 mM 3-ABA inhibited the characteristic ladder pattern in DNA gel analysis seen in apoptosis of retinal neurons after ischemia/reperfusion. Hence, PARP may be involved in retinal cell loss after ischemia/reperfusion insult probably through the apoptotic pathway.
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PMID:The effect of 3-aminobenzamide, an inhibitor of poly-ADP-ribose polymerase, on ischemia/reperfusion damage in rat retina. 914 32

Intranasal Herpes simplex virus type 1 (HSV-1) infection of mice caused pneumonia. Manifestations of the disease included: histological pneumonitis, pulmonary influx of lymphocytes, decreased pulmonary compliance, and decreased survival. Immunohistochemical staining demonstrated iNOS induction and the nitrotyrosine antigen in the lungs of infected, but not uninfected mice, suggesting that nitric oxide contributes to the development of pneumonia. To elucidate the role of nitric oxide in the pathogenesis of HSV-1 pneumonia, infected mice were treated either with the inhibitor of nitric oxide synthase activity, N(G)-monomethyl-L-arginine (L-NMMA), or, as a control, with PBS or D-NMMA. L-NMMA treatment decreased the histological evidence of pneumonia and reduced the bronchoalveolar lavage lymphocyte number to one-quarter of the total measured in control-treated mice. L-NMMA treatment significantly improved survival and pulmonary compliance of HSV-1-infected mice. Strikingly, the L-NMMA-mediated suppression of pneumonia occurred despite the presence of a 17-fold higher pulmonary viral titer. Taken together, these data demonstrated a previously unrecognized role of nitric oxide in HSV-1-induced pneumonia. Of note, suppression of pneumonia occurred despite higher pulmonary virus content; therefore, our data suggest that HSV-1 pneumonia is due to aspects of the inflammatory response rather than to direct viral cytopathic effects.
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PMID:Suppression of herpes simplex virus type 1 (HSV-1)-induced pneumonia in mice by inhibition of inducible nitric oxide synthase (iNOS, NOS2). 915 90

We investigated the effects of NG-nitro-L-arginine-methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on bone metastasis of human breast cancer, MDA-231 cells. Tumor cells (2 x 10(5) cells in 0.2 ml of phosphate-buffered saline; PBS) were injected through the diaphragm into the left ventricle of the heart of laparotomized nude mice (male 5-week-old ICR-nu/nu). L-NAME (2 mg/mouse/injection in 0.1 ml of PBS) was given intraperitoneally to mice 6 h and 3 h before and immediately, 3 h, 6 h, 18 h and 21 h after the intracardiac injection of tumor cells. As a control, 0.1 ml of PBS was injected instead of L-NAME. The effect of NG-nitro-D-arginine-methyl ester (D-NAME; 2 mg/mouse/injection), an inactive analogue of L-NAME, was also investigated to evaluate the specificity of L-NAME action. Radiographical examination 31 days after the tumor-cell injection showed that the incidence and number of osteolytic bone metastases and the number of bones with metastasis in L-NAME-treated mice were significantly reduced compared with those in PBS-treated mice (P < 0.05). The differences between PBS-treated and D-NAME-treated mice were not significant. Our findings suggest that specific and appropriate NOS inhibitors may represent a new pharmacological approach to therapy for cancer patients at risk of developing osteolytic bone metastases.
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PMID:NG-nitro-L-arginine methyl ester inhibits bone metastasis after modified intracardiac injection of human breast cancer cells in a nude mouse model. 936 34

Curcumin is a naturally occurring, dietary polyphenolic phytochemical that is under preclinical trial evaluation for cancer preventive drug development and whose working pharmacological actions include anti-inflammation. With respect to inflammation, in vitro, it inhibits the activation of free radical-activated transcription factors, such as nuclear factor kappaB (NFkappaB) and AP-1, and reduces the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta), and interleukin-8. Inducible nitric oxide synthase (iNOS) is an inflammation-induced enzyme that catalyzes the production of nitric oxide (NO), a molecule that may lead to carcinogenesis. Here, we report that in ex vivo cultured BALB/c mouse peritoneal macrophages, 1-20 microM of curcumin reduced the production of iNOS mRNA in a concentration-dependent manner. Furthermore, we demonstrated that, in vivo, two oral treatments of 0.5 mL of a 10-microM solution of curcumin (92 ng/g of body weight) reduced iNOS mRNA expression in the livers of lipopolysaccharide(LPS)-injected mice by 50-70%. Although many hold that curcumin needs to be given at dosages that are unattainable through diet to produce an in vivo effect, we were able to obtain potency at nanomoles per gram of body weight. This efficacy is associated with two modifications in our preparation and feeding regimen: 1) an aqueous solution of curcumin was prepared by initially dissolving the compound in 0.5 N NaOH and then immediately diluting it in PBS; and 2) mice were fed curcumin at dusk after fasting. Inhibition was not observed in mice that were fed ad lib., suggesting that food intake may interfere with the absorption of curcumin.
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PMID:In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with anti-inflammatory properties. 971 15

After transient cerebral ischemia in fetal sheep, delayed disruptions in cerebral energetics are represented by a delayed increase in cortical impedance, a progressive decrease in the concentration of oxidized cytochrome oxidase as measured by near-infrared spectroscopy, and cortical seizures. Because the production of nitric oxide (NO), a potent mediator of neuronal death, is increased during this phase, the present study investigated whether inhibition of NO synthesis could ameliorate the delayed disruption in cerebral energetics. Eleven late gestation fetal sheep were subjected to 30 min of transient cerebral ischemia in utero. Two hours later, the treatment group (n = 5) received a continuous infusion of N(G)-nitro-L-arginine, a competitive inhibitor of NO synthase, whereas the control group (n = 6) received PBS. Changes in concentration of oxidized cytochrome oxidase, cortical impedance, and electrocortical activity were observed for 3 d. A delayed increase in cortical impedance of similar magnitude and duration commenced at 14+/-4 h in the control and at 15+/-3 h in the treatment groups. The progressive decrease in oxidized cytochrome oxidase signal, by -2.2+/-0.2 micromol/L in the control and -2.0+/-0.4 micromol/L in the treatment group at 72 h postischemia, was similar in both groups. In both groups, delayed cortical seizures were indicated by intense low-frequency electrocortical activity. In the treatment group, duration of cortical seizures was increased and the intensity of the final electrocortical activity was more depressed (-19+/-1 dB versus -10+/-2 dB). The results indicate that after cerebral ischemia in fetal sheep, NO synthase inhibition does not ameliorate the delayed disruptions in cerebral energetics. However, the effect of NO synthase inhibition on delayed cortical seizures may improve our understanding of the role of NO during this phase.
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PMID:Nitric oxide synthase inhibition and delayed cerebral injury after severe cerebral ischemia in fetal sheep. 1040 Jan 27

We tested the hypothesis that NO synthase inhibition alters proinflammatory cytokine expression during acute lung injury in mice. Five-week-old CD-1 mice were pretreated with l-NAME or d-NAME and then received an intratracheal injection of endotoxin (or PBS). TNF-alpha and IL-6 ELISAs and RT-PCR were performed on lung homogenates sampled 6 h later. l-NAME increased TNF-alpha and IL-6 protein and mRNA expression in lungs. Immunostaining demonstrated that TNF-alpha was expressed predominantly by macrophages in the lung. l-NAME did not alter pulmonary macrophage concentration. To better understand the effect of NO synthase inhibition, elicited murine peritoneal macrophages were stimulated in vitro with LPS after addition of l-NAME, d-NAME, nitroprusside, or control. Nuclear proteins were extracted 3 h later and electrophoretic mobility shift and supershift assays were performed using radiolabeled NF-kappaB consensus sequence oligonucleotides. Endotoxin increased NF-kappaB p50/p65 heterodimer binding. Binding was further increased by l-NAME and decreased by nitroprusside. The effect of nitroprusside was not blocked by guanylate cyclase inhibition. We conclude that, in endotoxin-induced acute lung injury, NO synthase inhibition increases proinflammatory cytokine protein and mRNA expression in part because NO decreases the amount of NF-kappaB available for binding to the regulatory region of proinflammatory cytokine genes.
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PMID:Modulation of proinflammatory cytokines by nitric oxide in murine acute lung injury. 1043 Jul 48


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